Evaluating the feasibility of a multicenter teleneonatology clinical effectiveness trial.

BACKGROUND: Our research consortium is preparing for a prospective multicenter trial evaluating the impact of teleneonatology on the health outcomes of at-risk neonates born in community hospitals. We completed a 6-month pilot study to determine the feasibility of the trial protocol. METHODS: Four neonatal intensive care units ("hubs") and four community hospitals ("spokes") participated in the pilot-forming four hub-spoke dyads. Two hub-spoke dyads implemented synchronous, audio-video telemedicine consultations with a neonatologist ("teleneonatology"). The primary outcome was a composite feasibility score that included one point for each of the following: site retention, on-time screening log completion, no eligibility errors, on-time data submission, and sponsor site-dyad meeting attendance (score range 0-5). RESULTS: For the 20 hub-spoke dyad months, the mean (range) composite feasibility score was 4.6 (4, 5). All sites were retained during the pilot. Ninety percent (18/20) of screening logs were completed on time. The eligibility error rate was 0.2% (3/1809). On-time data submission rate was 88.4% (84/95 case report forms). Eighty-five percent (17/20) of sponsor site-dyad meetings were attended by both hub and spoke site staff. CONCLUSIONS: A multicenter teleneonatology clinical effectiveness trial is feasible. Learnings from the pilot study may improve the likelihood of success of the main trial. IMPACT: A prospective, multicenter clinical trial evaluating the impact of teleneonatology on the early health outcomes of at-risk neonates born in community hospitals is feasible. A multidimensional composite feasibility score, which includes processes and procedures fundamental to completing a clinical trial, is useful for quantitatively measuring pilot study success. A pilot study allows the investigative team to test trial methods and materials to identify what works well or requires modification. Learnings from a pilot study may improve the quality and efficiency of the main effectiveness trial.

Introduction of Amplitude-Integrated Electroencephalography (aEEG) Monitoring in a Level 2 NICU: Improving the Quality of Care for Neurologically At-Risk Newborns.

Amplitude-integrated electroencephalography (aEEG) is a bedside tool for continuous monitoring of brain activity with the possibility of real-time interpretation. Amplitude-integrated electroencephalography is routinely used in Canadian tertiary NICUs; however, its use in Level 2 NICUs has been limited. A bedside aEEG program was introduced in a Level 2 NICU in order to help facilitate the timely transfer of neurologically compromised infants and keep mother-infant dyads together where reassurance of appropriate neurological status could be attained. A monitoring guideline and educational program were developed. The introduction of aEEG monitoring enhanced the care provided to neurologically at-risk newborns. This experience can be used as a framework for other Level 2 NICUs who may wish to embark upon a similar initiative.

Callosal septa express guidance cues and are paramedian guideposts for human corpus callosum development.

The early development and growth of the corpus callosum are supported by several midline transient structures in mammals that include callosal septa (CS), which are present only in the second half of gestation in humans. Here we provide new data that support the guidance role of CS in corpus callosum development, derived from the analysis of 46 postmortem fetal brains, ranging in age from 16 to 40 post conception weeks (PCW). Using immunohistochemical methods, we show the expression pattern of guidance cues ephrinA4 and neogenin, extracellular protein fibronectin, as well as non-activated microglia in the CS. We found that the dynamic changes in expression of guidance cues, cellular and extracellular matrix constituents in the CS correlate well with the growth course of the corpus callosum at midsagittal level. The CS reach and maintain their developmental maximum between 20 and 26 PCW and can be visualized as hypointense structures in the ventral callosal portion with ex vivo (in vitro) T2-weighted 3T magnetic resonance imaging (MRI). The maximum of septal development overlaps with an increase in the callosal midsagittal area, whereas the slow, gradual resolution of CS coincides with a plateau of midsagittal callosal growth. The recognition of CS existence in human fetal brain and the ability to visualize them by ex vivoMRI attributes a potential diagnostic value to these transient structures, as advancement in imaging technologies will likely also enable in vivoMRI visualization of the CS in the near future.

Clinical and Imaging Findings in an Infant With Zika Embryopathy.

Recent Zika virus (ZIKV) outbreaks have been associated with an increased incidence of neonatal microcephaly. Subsequently, tropism for the brain was established in human fetal brain tissue. We present the first congenital ZIKV infection in the United States, confirmed by high ZIKV immunoglobulin M antibody titers in serum and cerebrospinal fluid. The phenotypic characteristics of the patient fall within fetal brain disruption sequence, suggesting impaired brain development in the second half of gestation. Brain imaging revealed an almost agyric brain with diffuse parenchymal calcifications, hydrocephalus ex vacuo, and cerebellar hypoplasia. Ophthalmologic examination revealed macular pigment stippling and optic nerve atrophy. Liver, lungs, heart, and bone marrow were not affected. The patient had progressive neurologic deterioration in the first month of life. The discovery of ZIKV infection in human fetal brain tissue along with serologic confirmation proves the vertical transmission of ZIKV. Therefore, ZIKV has joined the group of congenital infections.

Implementation of an ultrasound-guided approach for arterial line placements in neonates-quality improvement project.

OBJECTIVE: Our goal was to improve placement success rates for peripheral arterial line (PAL) placements by introducing an ultrasound-guided (USg) approach. Our aim was to maintain success rates over 70% within 18 months. STUDY DESIGN: Interventions included development of a training curriculum, and procedure standardization. Among 302 patients, 115 underwent USg catheter placement; the traditional method was used in 187 patients. Outcome measures were first-attempt and overall success rates. Process measures were proportion of PALs placed under US guidance, trainer availability, and trainee sign-off. Line complications were balancing measures. Statistical process control charts were used to monitor metrics. RESULTS: Sustained improvement was seen with the USg approach. The USg approach had first and overall attempt success by the trainers (i.e., independent users) of 83.7% (77/92) and 96.5% (111/115), compared to 50.3% (82/163) and 73.8% (138/187) with the traditional approach. CONCLUSION: Introducing the USg approach had a significant impact on PAL placement success in neonatal patients.

Age-dependent anticonvulsant actions of perampanel and brivaracetam in the methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) model of seizures in developing rats.

BACKGROUND: The antiseizure drugs commonly used as first- and second-line treatments for neonatal seizures display poor efficacy. Thus, drug mechanisms of action that differ from these typical agents might provide better seizure control. Perampanel, an AMPA-receptor antagonist, and brivaracetam, a SV2A ligand, might fill that role. METHODS: We utilized methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) to evoke seizures in rats to assess the efficacy of perampanel and brivaracetam treatment in clinically relevant doses. RESULTS: In postnatal day (P)10 rats, neither perampanel nor brivaracetam suppressed seizure activity. By contrast, in P21 rats, both drugs decreased the severity of seizures. This effect was evident at the 20 and 40 mg/kg doses of brivaracetam and at the 0.9 and 2.7 mg/kg doses of perampanel. CONCLUSIONS: These data indicate that while the efficacy of these drugs may be limited for neonatal seizures, their efficacy increases over early postnatal development.

Magnetic resonance findings in a neonate with nonketotic hyperglycinemia: case report.

We present brain imaging and spectroscopy data in a neonate with a confirmed classic form of nonketotic hyperglycinemia (NKH), an autosomal-recessive metabolic disorder characterized by accumulation of glycine. To our knowledge, this is the first report of such complete analysis of the changes seen on conventional magnetic resonance imaging, diffusion-weighted imaging, and magnetic resonance spectroscopy at such an early age. The findings in a neonate are consistent with reports in older children with NKH, confirming that pathological changes typical for NKH can be seen in the first postnatal week.

Changes of the corpus callosum in children who suffered perinatal injury of the periventricular crossroads of pathways.

There is a high incidence of periventricular leukomalacia, caused by hypoxia-ischemia, in preterm infants. These lesions damage the periventricular crossroads of commissural, projection and associative pathways, which are in a close topographical relationship with the lateral ventricles. We explored to what extent abnormalities of echogenicity of the periventricular crossroads correlate with changes in size of the corpus callosum. Our study included nine infants (gestation from 26-41 weeks; birth weight between 938-4450 grams) with perinatal brain injury. Periventricular areas, which topographically correspond to the frontal, main and occipital crossroad, were readily visualized by cranial ultrasound scans, performed during the first two weeks after birth. Corpus callosum mediosagittal area measurements were performed using magnetic resonance images, acquired between the first and sixth postnatal month (postmenstrual age 40-49 weeks). We found a statistically significant correlation between the increased echogenicity in the crossroad areas and the decrease of the corpus callosum midsagittal area (p < 0.05). This supports the hypothesis that callosal fibers can be damaged, during growth through the periventricular crossroads of pathways.

Perinatal findings in a patient with a novel large chromosome 19p deletion.

We describe the prenatal and postnatal course of an infant with a large 19p deletion. Cases such as ours will improve the knowledge of specific gene functions for every medical specialist. The goal is to allow for a more rapid diagnosis, accurate prognosis and to decrease the likelihood of complications.

Perinatal and early postnatal reorganization of the subplate and related cellular compartments in the human cerebral wall as revealed by histological and MRI approaches.

We analyzed the developmental history of the subplate and related cellular compartments of the prenatal and early postnatal human cerebrum by combining postmortem histological analysis with in vivo MRI. Histological analysis was performed on 21 postmortem brains (age range: 26 postconceptional weeks to 6.5 years) using Nissl staining, AChE-histochemistry, PAS-Alcian blue histochemistry, Gallyas' silver impregnation, and immunocytochemistry for MAP2, synaptophysin, neurofilament, chondroitin sulfate, fibronectin, and myelin basic protein. The histological findings were correlated with in vivo MRI findings obtained in 30 age-matched fetuses, infants, and children. We analyzed developmental reorganization of major cellular (cell bodies, growing axons) and extracellular (extracellular matrix) components of the subplate and the developing cortex/white matter interface. We found that perinatal and postnatal reorganization of these tissue components is protracted (extending into the second year of life) and characterized by well-delineated, transient and previously undescribed structural and molecular changes at the cortex/white matter interface. The findings of this study are clinically relevant because they may inform and guide a proper interpretation of highly dynamic and hitherto puzzling changes of cortical thickness and cortical/white matter interface as described in current in vivo MRI studies.

Growth of the human corpus callosum: modular and laminar morphogenetic zones.

The purpose of this focused review is to present and discuss recent data on the changing organization of cerebral midline structures that support the growth and development of the largest commissure in humans, the corpus callosum. We will put an emphasis on the callosal growth during the period between 20 and 45 postconceptual weeks (PCW) and focus on the advantages of a correlated histological/magnetic resonance imaging (MRI) approach. The midline structures that mediate development of the corpus callosum in rodents, also mediate its early growth in humans. However, later phases of callosal growth in humans show additional medial transient structures: grooves made up of callosal septa and the subcallosal zone. These modular (septa) and laminar (subcallosal zone) structures enable the growth of axons along the ventral callosal tier after 18 PCW, during the rapid increase in size of the callosal midsagittal cross-section area. Glial fibrillary acidic protein positive cells, neurons, guidance molecule semaphorin3A in cells and extracellular matrix (ECM), and chondroitin sulfate proteoglycan in the ECM have been identified along the ventral callosal tier in the protruding septa and subcallosal zone. Postmortem MRI at 3 T can demonstrate transient structures based on higher water content in ECM, and give us the possibility to follow the growth of the corpus callosum in vivo, due to the characteristic MR signal. Knowledge about structural properties of midline morphogenetic structures may facilitate analysis of the development of interhemispheric connections in the normal and abnormal fetal human brain.